5-aza-2′-deoxycytidine induces telomere dysfunction in breast cancer cells - 21/08/24
Abstract |
Aims |
Azacitidine, a drug that epigenetically modifies DNA, is widely used to treat haematological malignancies. However, at low doses, it demethylates DNA, and as a result, can alter gene expression. In our previous publication, we showed that low doses of azacitidine induce telomere length elongation in breast cancer cells. In this study, we aim to identify the mechanisms which lead to telomere length increases.
Methods |
Breast cancer cell lines representing different molecular sub-types were exposed to 5-aza-2′-deoxycytidine (5-aza) in 2 and 3D cultures, followed by DNA, RNA, and protein extractions. Samples were then analysed for telomere length, DNA damage, telomerase, and ALT activity.
Results |
We show that treatment of the cell lines with 5-aza for 72 h induced DNA damage at the telomeres and increased ALT activity 3-fold. We also identified a gene, POLD3, which may be involved in the ALT activity seen after treatment.
Conclusion |
Our results indicate that while 5-aza is a useful drug for treating haematological cancers, surviving cancer cells that have been exposed to lower doses of the drug may activate mechanisms such as ALT. This could lead to cancer cell survival and possible resistance to 5-aza clinically.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Confirmation that 5-aza-2′-deoxycytidine induces telomere length increase in both 2D and 3D cell cultures. |
• | 5-aza induces DNA damage at the telomeres in breast cancer cell lines. |
• | ALT activation, a mechanism used to maintain telomere length, was detected 72 h after 5-aza treatment. |
• | mRNA expression levels for the POLD3 gene increased 10–20-fold in all cell lines tested. |
• | We propose that POLD3, activates a DNA recombination process (ALT) which increases telomere length in calls exposed to 5-aza. |
Keywords : Telomere, Telomerase, ALT, Breast cancer
Plan
Vol 178
Article 117173- septembre 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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